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Neuropsychologia xxx (2003) xxx–xxxRapid publication<strong>Dissociable</strong> <strong>correlates</strong> <strong>of</strong> <strong>recollection</strong> <strong>and</strong> <strong>familiarity</strong>within the medial temporal lobesCharan Ranganath a,∗ , Andrew P. Yonelinas a , Michael X Cohen a ,Christine J. Dy b , Sabrina M. Tom b , Mark D’Esposito ba Center for Neuroscience <strong>and</strong> Department <strong>of</strong> Psychology, University <strong>of</strong> California at Davis, 1544 Newton Ct., Davis, CA 95616, USAb Henry H. Wheeler Jr. Brain Imaging Center, Helen Wills Neuroscience Institute <strong>and</strong> Department <strong>of</strong> Psychology,University <strong>of</strong> California at Berkeley, Berkeley, CA, USAReceived 4 June 2003; accepted 22 July 2003AbstractRegions in the medial temporal lobes (MTL) have long been implicated in the formation <strong>of</strong> new memories for events, however, it isunclear whether different MTL subregions support different memory processes. Here, we used event-related functional magnetic resonanceimaging (fMRI) to examine the degree to which two recognition memory processes—<strong>recollection</strong> <strong>and</strong> <strong>familiarity</strong>—were supported bydifferent MTL subregions. Results showed that encoding activity in the rhinal cortex selectively predicted <strong>familiarity</strong>-based recognition,whereas, activity in the hippocampus <strong>and</strong> posterior parahippocampal cortex selectively predicted <strong>recollection</strong>. Collectively, these resultssupport the view that different subregions within the MTL memory system implement unique encoding processes that differentially support<strong>familiarity</strong> <strong>and</strong> <strong>recollection</strong>.© 2003 Elsevier Ltd. All rights reserved.Keywords: Prefrontal; Inferior; Frontal; Hippocampus; Parahippocampal; Rhinal; Perirhinal; Medial; Temporal; Long-term; Episodic; Memory; Encoding;Subsequent; fMRI; Neuroimaging; Human1. IntroductionIt is well established that extensive damage to the medialtemporal lobes (MTL) causes severe <strong>and</strong> relatively specificimpairments in the ability to form new declarative memories.For example, amnesic patients with extensive MTLdamage have been shown to exhibit deficits on explicit tests<strong>of</strong> free recall <strong>and</strong> recognition (Moscovitch & McAndrews,2002; Yonelinas, Kroll, Dobbins, Lazzara, & Knight, 1998)but show intact performance on numerous measures <strong>of</strong> unconsciouslearning processes, such as skill learning, simpleclassical conditioning, <strong>and</strong> perceptual priming (Squire &Knowlton, 2000). The MTL regions that appear to be mostcritical for declarative memory formation are the hippocampalregion (i.e., the dentate gyrus, CA 1–3, <strong>and</strong> the subicularcomplex) <strong>and</strong> the cortex <strong>of</strong> the parahippocampal gyrus(the entorhinal, perirhinal, <strong>and</strong> parahippocampal cortices).Based on anatomical differences between the hippocampal<strong>and</strong> parahippocampal regions (Lavanex & Amaral, 2000),∗ Corresponding author. Tel.: +1-530-757-8750; fax: +1-530-757-8827.E-mail address: cranganath@ucdavis.edu (C. Ranganath).URL: http://www.dynamicmemorylab.org.several researchers have proposed that these subregions mayimplement distinct memory processes (Aggleton & Brown,1999; Eichenbaum & Cohen, 2001; O’Reilly & Norman,2002; O’Reilly & Rudy, 2001; Shastri, 2002). However, thecharacterization <strong>of</strong> how these regions might contribute todifferent aspects <strong>of</strong> declarative memory has been a topic <strong>of</strong>extensive controversy.Results from numerous behavioral studies have supportedthe view that declarative memory is supported by at leasttwo distinct processes: the assessment <strong>of</strong> an item’s <strong>familiarity</strong><strong>and</strong> the <strong>recollection</strong> <strong>of</strong> the context in which an itemwas encountered (Yonelinas, 2002). Based on an extensivereview <strong>of</strong> neuropsychological <strong>and</strong> neurophysiological studies<strong>of</strong> recognition memory in rats, monkeys, <strong>and</strong> humans,Aggleton <strong>and</strong> Brown (1999) recently proposed that thesetwo processes might depend on different MTL subregions.Specifically, these investigators hypothesized that, whereasthe hippocampus supports <strong>recollection</strong>, regions within theparahippocampal gyrus support <strong>familiarity</strong>-based recognition.Similar predictions have been made based on othermodels <strong>of</strong> cortico-hippocampal interaction (Eichenbaum &Cohen, 2001; O’Reilly & Norman, 2002; O’Reilly & Rudy,2001; Shastri, 2002).0028-3932/$ – see front matter © 2003 Elsevier Ltd. All rights reserved.doi:10.1016/j.neuropsychologia.2003.07.006
2 C. Ranganath et al. / Neuropsychologia xxx (2003) xxx–xxxOther investigators, while acknowledging potential heterogeneitybetween MTL subregions, have suggested thatthese subregions may support <strong>familiarity</strong> <strong>and</strong> <strong>recollection</strong>to an equivalent degree. For example, Squire <strong>and</strong>Knowlton (2000) have suggested that <strong>familiarity</strong> <strong>and</strong> <strong>recollection</strong>may be functionally distinct, but that they are bothforms <strong>of</strong> declarative memory that depend on integrated processingwithin the MTL. These investigators have suggestedthat dissociations between <strong>recollection</strong> <strong>and</strong> <strong>familiarity</strong> mayreflect the disproportional dependence <strong>of</strong> <strong>recollection</strong> onstrategic processing mediated by the prefrontal cortex (PFC)(Davidson & Glisky, 2002; Knowlton & Squire, 1995;Manns, Hopkins, Reed, Kitchener, & Squire, 2003). Consistentwith this view, several neuropsychological studiessuggest that recognition memory is relatively preserved inpatients with PFC lesions, whereas performance is impairedon free recall <strong>and</strong> source memory tests that are thought torely on <strong>recollection</strong> (for a review, see Ranganath & Knight,2003).Studies <strong>of</strong> amnesic patients with varying degrees <strong>of</strong> MTLdamage have yielded conflicting results regarding whetherdifferent MTL regions support <strong>recollection</strong> <strong>and</strong> <strong>familiarity</strong>.Results from some neuropsychological studies havesupported the view that the hippocampus is disproportionatelycritical for <strong>recollection</strong>, whereas parahippocampalregions can support <strong>familiarity</strong>-based recognition (Aggleton& Shaw, 1996; Baddeley, Vargha-Khadem, & Mishkin,2001; Duzel, Vargha-Khadem, Heinze, & Mishkin, 2001;Holdstock et al., 2002; Mayes, Holdstock, Isaac, Hunkin,& Roberts, 2002; Yonelinas et al., 2002). However, resultsfrom other studies have suggested a similar role forboth the hippocampus <strong>and</strong> parahippocampal regions in<strong>familiarity</strong>-based recognition <strong>and</strong> <strong>recollection</strong> (Manns et al.,2003; Stark & Squire, 2001, 2003).In light <strong>of</strong> the difficulties in precisely specifying thelocus <strong>and</strong> extent <strong>of</strong> lesions in amnesic patients, functionalneuroimaging studies can provide a critical source<strong>of</strong> evidence regarding the nature <strong>of</strong> encoding processesimplemented by different MTL subregions. Results fromhuman neuroimaging studies have generally shown thatencoding activity in the ventrolateral PFC, hippocampus,<strong>and</strong> the posterior parahippocampal cortex is enhanced forrecollected items relative to forgotten items (Brewer, Zhao,Desmond, Glover, & Gabrieli, 1998; Davachi, Mitchell, &Wagner, 2003; Davachi & Wagner, 2002; Fern<strong>and</strong>ez et al.,1999; Henson, Rugg, Shallice, Josephs, & Dolan, 1999;Kirchh<strong>of</strong>f, Wagner, Maril, & Stern, 2000; Otten,Henson, & Rugg, 2001; Reber et al., 2002; Strange, Otten,Josephs, Rugg, & Dolan, 2002) as well as items that arerecognized on the basis <strong>of</strong> <strong>familiarity</strong> (Brewer et al., 1998;Davachi et al., 2003; Henson et al., 1999). In contrast, robust<strong>correlates</strong> <strong>of</strong> <strong>familiarity</strong>-based recognition at encodinghave not been identified (but see Davachi et al., 2003).In previous neuroimaging studies, <strong>familiarity</strong>-related encodingactivations may have been elusive because recognitionmemory is usually treated as a categorical variable (e.g.,recollected versus recognized on the basis <strong>of</strong> <strong>familiarity</strong> versusforgotten). Thus, prior studies may have lacked adequatemeasurement sensitivity to detect changes <strong>of</strong> encoding activitythat covaried with incremental changes in subsequent<strong>familiarity</strong>. Behavioral studies have indicated that, although<strong>recollection</strong> can be categorical (i.e., some items are recollected,while others are not), <strong>familiarity</strong> varies in a more continuousnature (i.e., differences in <strong>familiarity</strong> are reflectedas a gradual change in recognition confidence; for a reviewsee Yonelinas, 2002). Accordingly, in order to measure theneural <strong>correlates</strong> <strong>of</strong> <strong>familiarity</strong>, it may be more appropriateto use measures <strong>of</strong> memory that are sensitive to continuouschanges in memory strength.In the present study, we used event-related functionalmagnetic resonance imaging (fMRI) to determine how encodingprocesses within MTL subregions are related to <strong>familiarity</strong><strong>and</strong> <strong>recollection</strong>. Subjects were scanned while theyencoded a list <strong>of</strong> visually presented words (Fig. 1A). Half<strong>of</strong> the words were presented in red <strong>and</strong> half were presentedin green. In a post-scan memory test, subjects were showna series <strong>of</strong> studied words <strong>and</strong> novel foils <strong>and</strong> asked to indicateon a 1–6 scale how confident they were that the itemwas studied (i.e., recognition confidence judgments), <strong>and</strong> toindicate whether the item was studied in red or green (i.e.,(A) ExperimentalDesignScan Phase:Size <strong>and</strong>Animacy JudgmentsPost-Scan:Confidence <strong>and</strong>Source Judgments(B) Behavioral ResultsProportion0.50.40.30.20.1850msNICKEL1150-13150ms6 3 2 5 1 656 5 6 3 2G RG G R RGGRR R GNew+Old850msDEER1 2 3 4 5 6"Definitely New" RecognitionConfidence"Definitely Old"Fig. 1. Experimental design <strong>and</strong> behavioral results. (A) Schematic depiction<strong>of</strong> the sequence <strong>of</strong> events in one scanning run. During scanning,subjects viewed a series <strong>of</strong> words, <strong>and</strong> made either an animacy or sizejudgment for each, depending on the color in which the word was shown.After the scan session, subjects made recognition confidence (1: definitelynew, ..., 6: definitely old) <strong>and</strong> source memory (red or green) judgmentsfor each word, <strong>and</strong> fMRI results during encoding were then analyzed as afunction <strong>of</strong> these measures. (B) Mean proportions <strong>of</strong> studied (“old”) <strong>and</strong>unstudied (“new”) items endorsed at each confidence level. Error barsdepict the st<strong>and</strong>ard error <strong>of</strong> the mean across subjects.
C. Ranganath et al. / Neuropsychologia xxx (2003) xxx–xxx 3source memory judgments). Because the red <strong>and</strong> green itemswere presented in a mixed order during the study list theyshould be equally familiar at time <strong>of</strong> test, <strong>and</strong> it would beunlikely that subjects could use <strong>familiarity</strong> to make sourcejudgments. Thus, differences in activation between itemsleading to accurate compared to inaccurate source judgmentswould reflect the encoding processes that are specific to <strong>recollection</strong>.In contrast, prior behavioral findings suggest that<strong>recollection</strong> leads to high confidence recognition responseswhereas <strong>familiarity</strong> contributes to the entire range <strong>of</strong> recognitionconfidence in a graded manner (Yonelinas, 2001). Accordingly,<strong>familiarity</strong> was indexed as a continuous increaseacross confidence ratings 1–5.2. Materials <strong>and</strong> methods2.1. ParticipantsThirteen neurologically intact right-h<strong>and</strong>ed native Englishspeakers (seven females) aged 18–25 years participated inthe study. These volunteers were recruited from the UCBerkeley <strong>and</strong> UC Davis student communities <strong>and</strong> were financiallycompensated for their participation.2.2. MaterialsSeven hundred <strong>and</strong> twenty nouns were selected from theMRC Psycholinguistic Database. All words were highly imageable(ratings greater then 500 on a scale from 100–700)<strong>and</strong> were selected to be unambiguous with respect to whetherthey were smaller/bigger than a shoebox <strong>and</strong> whether theywere living/nonliving. Half <strong>of</strong> the words were r<strong>and</strong>omly selectedto serve as study items, with the constraint that theywere balanced with the non-studied items for word frequency<strong>and</strong> word imageability.2.3. ProcedureAt the beginning <strong>of</strong> the experimental session, participantswere scanned during performance <strong>of</strong> a visuomotor responsetask, in which a bimanual button press was made in responseto a flashing checkerboard presented once every 20 s.Results from this task were used to derive an individualhemodynamic response function (HRF) (Aguirre, Zarahn, &D’Esposito, 1998).Next, subjects performed six runs <strong>of</strong> word encoding. Ineach run, 60 words were presented at the center <strong>of</strong> the screen(half in red <strong>and</strong> half in green presented in a r<strong>and</strong>om order).Each word was presented for 850 ms followed by a fixationcross that was jittered from 1150 to 13,150 ms in 2000 msintervals. To ensure that subjects later remembered the color<strong>of</strong> the items they were instructed that if the word was presentedin green they were to decide whether it referred toan object that could fit in a shoebox (size judgment). If theword was presented in red, they were to indicate whether itreferred to a living or nonliving object (animacy judgment).Yes/no decisions were made by pressing one <strong>of</strong> two buttonson a four-button fiber optic response device.Immediately after the scanning session, subjects were presentedwith a self-paced recognition memory test containinga r<strong>and</strong>om mixture <strong>of</strong> studied words (360) <strong>and</strong> new words(360). The items were presented <strong>and</strong> responses collected ona laptop computer. For each word, subjects first rated howconfident they were that the item was studied (1: sure it isnew, ..., 6: sure it is old). They were instructed to spreadtheir responses across the entire response scale, being carefulto use all the response categories. For each item, theywere also required to make a source memory judgment, indicatingif the item was initially studied in green (i.e., thesize judgment task) or red (i.e., the animacy task). If subjectsfelt they were unsure <strong>of</strong> the color <strong>of</strong> the word at study or ifthey felt that the word was not studied, they were instructedto guess.2.4. MRI acquisition <strong>and</strong> processingMRI data for seven volunteers were collected on a 1.5TPicker Medical Systems scanner at the Martinez VA MedicalCenter. Functional imaging was performed using a gradientecho echoplanar imaging (EPI) sequence sensitive to bloodoxygenation level dependent (BOLD) contrast (TR = 2000,TE = 32, FOV = 240 mm, 64 × 64 matrix). Each functionalvolume consisted <strong>of</strong> 20 contiguous 5 mm axial slicesoriented parallel to the AC–PC line. In addition, co-planar<strong>and</strong> high-resolution T1-weighted localizer images were alsoacquired. MRI data from six volunteers were collected on a1.5T GE Signa scanner at the UC Davis Research ImagingCenter. Functional imaging at this site was also done with agradient echo EPI sequence (TR = 2000, TE = 40, FOV =240 mm, 64×64 matrix), with each volume consisting <strong>of</strong> 24contiguous 5 mm axial slices. Co-planar <strong>and</strong> high-resolutionT1-weighted images were also acquired for each <strong>of</strong> thesevolunteers. fMRI data processing for all subjects included:motion correction using a six-parameter, rigid-body transformationalgorithm provided by Statistical Parametric Mapping(SPM99) s<strong>of</strong>tware, calculation <strong>of</strong> the global signal <strong>and</strong>power spectrum for each scanning run, <strong>and</strong> normalization<strong>of</strong> the time-series <strong>of</strong> each voxel by its mean signal value toattenuate between-run scaling differences.2.5. Data analysisEvent-related BOLD responses were analyzed using amodified general linear model (Worsley & Friston, 1995).All models incorporated empirically derived estimates<strong>of</strong> intrinsic temporal autocorrelation (Zarahn, Aguirre, &D’Esposito, 1997), filters to attenuate frequencies above0.25 Hz <strong>and</strong> below 0.01 Hz, <strong>and</strong> covariates to model themean <strong>of</strong> each scanning run. RFs were estimated for eachsubject using empirically derived BOLD responses in thecentral sulcus during the visuomotor response task (Aguirre
4 C. Ranganath et al. / Neuropsychologia xxx (2003) xxx–xxxet al., 1998). These HRFs were used to model BOLD responsesto events in all subsequent analyses (Aguirre et al.,1998; Postle, Zarahn, & D’Esposito, 2000).Responses during encoding trials were analyzed both asa function <strong>of</strong> subsequent recognition confidence <strong>and</strong> as afunction <strong>of</strong> source memory accuracy. In the recognition confidenceanalyses, BOLD responses were modeled with sixseparate covariates corresponding to each subsequent recognitionconfidence category. In the source memory analyses,separate covariates were included to model responses towords subsequently judged “new” (i.e., words that evokeda 1, 2, or 3 confidence rating), words subsequently judged“old” (i.e., words that evoked a 4, 5, or 6 confidence rating),but for which the source memory judgment was incorrect,<strong>and</strong> words subsequently judged old for which the sourcememory judgment was correct.Results from single-subject analyses were then enteredinto second-level t-tests treating subjects as a r<strong>and</strong>om variable.For these analyses, images <strong>of</strong> parameter estimatesfor each contrast <strong>of</strong> interest (i.e., linear combinations <strong>of</strong>β values from the regression analyses described above)were spatially normalized to the template from the InternationalConsortium for Brain Mapping Project (Cocosco,Kollokian, Kwan, & Evans, 1997), resliced into 2 mmisotropic voxels, <strong>and</strong> spatially smoothed with an 8 mmGaussian filter using SPM99 s<strong>of</strong>tware. These normalized,smoothed subject-specific contrast images were then enteredinto a second-level group analysis—a one-sample t-test—inwhich the mean value across the group for each voxel wastested against zero. Significant regions <strong>of</strong> activation wereidentified using a two-tailed threshold <strong>of</strong> P
C. Ranganath et al. / Neuropsychologia xxx (2003) xxx–xxx 5Fig. 3. Subsequent <strong>recollection</strong> effects as indexed by source memory accuracy. (A) Two MTL regions that exhibited subsequent <strong>recollection</strong> effects—theposterior hippocampus (shown within the red square) <strong>and</strong> the posterior parahippocampal cortex (shown within the yellow square)—are overlaid onan averaged T1-weighted image. Plots <strong>of</strong> the parameter estimates (indexing response amplitude) for recognized items eliciting correct (filled bars) vs.incorrect source judgments (open bars) are shown for each <strong>of</strong> these regions. (B) Other regions <strong>of</strong> cortical activation are rendered on a template brain.ROI (similar results were obtained when the entire extent <strong>of</strong>activation was used to define each ROI). For these analyses,we additionally verified that similar effects were observedfor subjects at each imaging site.3. Results3.1. Behavioral resultsThe distributions <strong>of</strong> recognition confidence ratings forstudied <strong>and</strong> unstudied items are presented in Fig. 1B. Thefigure shows that the proportion <strong>of</strong> recognized items increasedmonotonically with recognition confidence. Fornon-recognized items (i.e., items eliciting a 1–3 confidenceresponse), mean source accuracy (mean = 50.9%, S.D. =6.7%) did not differ from chance [t(12)
6 C. Ranganath et al. / Neuropsychologia xxx (2003) xxx–xxxTable 1Regions exhibiting a subsequent <strong>familiarity</strong> effect, as indexed by recognitionconfidenceRegion BA X Y Z tL. anterior parahippocampal 36 −18 6 −34 5.45gyrusL. inferior frontal gyrus 44 −50 12 38 6.376/44 −54 4 32 5.56L. anterior superior frontal 10 −20 60 −2 5.26gyrusL. gyrus rectus 11 −16 26 −26 5.52R. anterior insula 34 18 14 7.94L. fusiform gyrus 37 −50 −60 −16 5.88L. inferior temporal gyrus 37 −50 −54 −8 5.55L. precenteral gyrus 6 −34 0 44 6.89L. superior frontal sulcus 6 −24 −8 54 5.74Supplementary motor area 8 0 24 46 9.616 −2 16 50 6.196 0 4 54 5.93L. inferior parietal lobule 40 −44 −36 36 6.36−46 −44 38 5.34−56 −30 38 6.27−44 −40 56 7.56L. superior parietal lobule 7 −22 −68 54 6.43−28 −58 52 4.91L. lingual gyrus 18 −10 −90 −16 6.4−14 −78 −14 6.37L. cuneus 19 −26 −76 40 6.06R. postcentral gyrus 2 46 −38 52 5.9844 −32 62 5.8152 −22 54 5.64L. postcentral gyrus 3 −48 −24 54 5.82R. cerebellum 16 −70 −18 7.44R. caudate nucleus (head) 8 4 −6 5.31L. anterior thalamus −6 −4 8 5.16L. medial thalamus −4 −18 14 5.02R. globus pallidus 18 −4 8 4.89Note: These regions exhibited a linear relationship between encodingactivation <strong>and</strong> subsequent recognition confidence across levels 1–5. R:right; L: left; BA: Brodmann’s area.from any <strong>of</strong> the analyses did not change the pattern <strong>of</strong>results.)3.2. fMRI resultsIn order to identify regions whose encoding activity wasassociated with <strong>familiarity</strong> we examined the correlation betweenencoding activation <strong>and</strong> response confidence ratings1–5 (i.e., computing a linear contrast <strong>of</strong> parameter estimatesas follows: “5”: +2; “4”: +1; “3”: 0; “2”: −1; “1”: −2).In order to identify regions related to <strong>recollection</strong>, we examinedregions in which encoding activation for recognizeditems was significantly increased for items that elicited correctcompared to incorrect source judgments.Results from these analyses are summarized in Tables 1<strong>and</strong> 2. As shown in Fig. 2A, a region showing <strong>familiarity</strong>-Table 2Regions exhibiting a subsequent <strong>recollection</strong> effect, as indexed by sourcememory accuracyRegion BA X Y Z tR. posterior hippocampus 26 −30 −4 8.71R. posterior parahippocampal 37 30 −40 −16 5.33gyrusL. inferior frontal gyrus 45 −52 38 16 5.976/44 −48 0 28 5.43R. inferior frontal gyrus 44 48 16 30 4.86L. lateral orbital gyrus 47 −36 24 −12 5.63R. inferior temporal gyrus 37 50 −56 −12 5.83R. fusiform gyrus 37 44 −52 −20 4.98L. superior temporal gyrus 38 −48 4 −10 6.32−48 12 −14 4.9−38 0 −12 8.7R. superior temporal gyrus 38 64 6 −10 5.87L. anterior insula −32 18 −8 5.93R. precentral gyrus 6 46 0 60 5.04L. precentral gyrus 6 −40 −2 30 5.08L. inferior parietal lobule 40 −52 −30 34 6.41−40 −40 48 5.18R. inferior parietal lobule 40 48 −38 40 6.7236 −58 44 6.36L. cuneus 17 −4 −94 8 8.62L. mediodorsal thalamus −16 −10 8 5.54Note: These regions exhibited greater encoding activation for subsequentlyrecognized words that elicited correct source judgments than for subsequentlyrecognized words that elicited incorrect source judgments. R:right; L: left; BA: Brodmann’s area.related encoding activation was observed in the left anteriormedial parahippocampal gyrus (BA 36). Based on thelocation <strong>of</strong> this activation, <strong>and</strong> inspection <strong>of</strong> single-subjectdata, this region most likely corresponds to the rhinal cortex(i.e., either lying in peri- or ento-rhinal cortex (Amaral,1999)). No other MTL region exhibited significant <strong>familiarity</strong>effects. However, regions in the hippocampus <strong>and</strong> inthe right posterior collateral sulcus (spanning the posteriorparahippocampal <strong>and</strong> fusiform gyri), shown in Fig. 3A, exhibitedsubsequent <strong>recollection</strong> effects. In addition, anotherregion <strong>of</strong> activation related to <strong>recollection</strong> was observed inthe MTL (MNI coordinates: 36, −24, −20), but upon inspection<strong>of</strong> its location on the averaged T1 image or on thesingle-subject T1-weighted images, it was unclear whetherthis area was within the hippocampus or within the posteriorparahippocampal cortex. In light <strong>of</strong> this ambiguity, wedo not comment further on this area.The results from the above analyses suggest that differentMTL subregions exhibited different patterns <strong>of</strong> subsequentmemory effects. However, as we have previously shown(Ranganath & D’Esposito, 2001; Ranganath, Johnson, &D’Esposito, 2003), it is important to distinguish whetherdifferent patterns <strong>of</strong> activation in thresholded statisticalmaps reflect qualitative or merely quantitative differences in
C. Ranganath et al. / Neuropsychologia xxx (2003) xxx–xxx 7response properties. Thus, to more extensively characterizethe patterns <strong>of</strong> encoding activity within MTL subregions,ROIs were defined within the left rhinal, right hippocampal,<strong>and</strong> right posterior parahippocampal/fusiform regionsidentified above (see Section 2 for details).First, we investigated whether the apparent dissociationobserved between the three MTL subregions may haveemerged as a result <strong>of</strong> the stringent statistical thresholdsused to identify subsequent memory effects. Results <strong>of</strong>exploratory analyses within the rhinal cortex ROI did notreveal any trend toward greater activation for recognizeditems that elicited correct versus incorrect source judgments[t(11) =−1.32, P>0.2]. Thus, we found no indicationsthat activation in this region was predictive <strong>of</strong> <strong>recollection</strong>.Likewise, exploratory analyses within the hippocampus <strong>and</strong>parahippocampal/fusiform ROIs did not reveal a reliablerelationship between encoding activation <strong>and</strong> subsequent<strong>familiarity</strong> [hippocampus: t(12) = 1.79, P = 0.10; parahippocampal/fusiform:t(12)
8 C. Ranganath et al. / Neuropsychologia xxx (2003) xxx–xxxLeft Ventrolateral PFC (BA 6/44)(A) 0.0000016(B) 0.0025Parameter Estimate0.00000120.00000080.0000004Parameter Estimate0.00200.00150.00100.00050.00000001 2 3 4 5 6Recognition Confidence0.0000SourceIncorrectSourceCorrectFig. 5. Subsequent memory effects observed in left ventrolateral PFC (BA 6/44). (A) Encoding activation is plotted as a function <strong>of</strong> subsequent recognitionconfidence for the local maxima within left BA 6/44 (X =−54, Y = 4, Z = 32). (B) Encoding activation is plotted for recognized items eliciting correct(filled bar) vs. incorrect (open bar) source judgments for the local maxima within left BA 6/44 (X = 48, Y = 0, Z = 28). Error bars depict the st<strong>and</strong>arderror <strong>of</strong> the mean across subjects.4. DiscussionIn the present study, we used multiple methods to examinethe neural <strong>correlates</strong> <strong>of</strong> memory formation within specificMTL subregions. Recognition confidence was explored as aparametric index <strong>of</strong> subsequent memory, yielding a sensitivemeasure <strong>of</strong> <strong>familiarity</strong>-based recognition. In addition, sourcememory accuracy provided a measure <strong>of</strong> subjects’ ability torecollect qualitative information about study events. Our resultsrevealed that encoding activity in distinct MTL subregionswas differentially correlated with subsequent indices<strong>of</strong> <strong>familiarity</strong> <strong>and</strong> <strong>recollection</strong>. Furthermore, we observedthat encoding activity in regions <strong>of</strong> PFC predicted subsequent<strong>familiarity</strong> <strong>and</strong> <strong>recollection</strong>. We discuss these findings<strong>and</strong> their implications below.4.1. Distinct MTL subregions differentially contribute t<strong>of</strong>amiliarity <strong>and</strong> <strong>recollection</strong>As noted earlier, recent research has suggested thathippocampal <strong>and</strong> parahippocampal regions may implementdistinct encoding operations. Consistent with modelsproposing functional heterogeneity within the MTL(Aggleton & Brown, 1999; Eichenbaum & Cohen, 2001;O’Reilly & Norman, 2002; O’Reilly & Rudy, 2001;Shastri, 2002), we observed that encoding activity ina region in the left rhinal cortex specifically predicted<strong>familiarity</strong>-based recognition, but there was no indicationthat activity in this region was correlated with <strong>recollection</strong>.In contrast, encoding activity in regions in the posteriorhippocampus <strong>and</strong> posterior parahippocampal cortex specificallypredicted <strong>recollection</strong>, but activity in these regions didnot reliably covary with subjective recognition confidence.These findings add to accumulating evidence suggestive<strong>of</strong> a functional distinction between the hippocampus <strong>and</strong> therhinal cortex. For example, results from one fMRI study revealedgreater hippocampal <strong>and</strong> posterior parahippocampalactivation during retrieval <strong>of</strong> source information than duringitem-recognition (Yonelinas, Hopfinger, Buonocore, Kroll,& Baynes, 2001). Results from another study showed thathippocampal activity during memory retrieval was selectivelyenhanced during recognition <strong>of</strong> items that were recollectedrelative to items that were recognized on the basis <strong>of</strong><strong>familiarity</strong> (Eldridge, Knowlton, Furmanski, Bookheimer,& Engel, 2000). Finally, a recent analysis <strong>of</strong> results fromfour neuroimaging studies <strong>of</strong> memory retrieval showed thatactivity in the rhinal cortex differentiated between novel<strong>and</strong> familiar items, but was not sensitive to whether informationabout these items was recollected (Henson, Cansino,Herron, Robb, & Rugg, 2003). These findings suggest thatrhinal <strong>and</strong> hippocampal regions exhibit dissociable patterns<strong>of</strong> activity at retrieval.Concurrent with our investigation, another research groupalso used event-related fMRI to investigate the relationshipbetween encoding activity in MTL subregions <strong>and</strong> sourcememory accuracy. Davachi et al. (2003) examined activityduring a deep (visual imagery) encoding task that elicitedhigh levels <strong>of</strong> recognition memory <strong>and</strong> a shallow (covert articulation)encoding task that elicited relatively poor memoryperformance. Their results showed that hippocampal activationfor deeply encoded items was selectively enhanced ifsubjects correctly recalled encountering the item in the deep
C. Ranganath et al. / Neuropsychologia xxx (2003) xxx–xxx 9encoding task. In contrast, perirhinal activation for deeplyencoded items was enhanced if these items were subsequentlyrecognized, regardless <strong>of</strong> whether subjects successfullyrecalled encountering them in the deep encoding task.Our results are consistent with the results <strong>of</strong> Davachi et al.(2003) suggesting that the hippocampus specifically contributesto source <strong>recollection</strong>. Our results further demonstratethat encoding activation in the rhinal cortex is directlyrelated to <strong>familiarity</strong>-based recognition confidence ratings,<strong>and</strong> that rhinal <strong>and</strong> hippocampal regions make qualitativelydistinct contributions to memory formation.The sharp contrast between rhinal <strong>and</strong> hippocampal encodingactivity observed here may seem surprising, giventhat most theoretical discussions <strong>of</strong> <strong>recollection</strong> <strong>and</strong> <strong>familiarity</strong>center around retrieval processing. Indeed, our findingsraise the question <strong>of</strong> what types <strong>of</strong> encoding processes mightbe mediated by these regions. One possibility is that, whereasthe rhinal <strong>and</strong> parahippocampal cortices encode the specificaspects <strong>of</strong> an event that can support <strong>familiarity</strong> in the absence<strong>of</strong> an adequate hippocampal representation, the hippocampusencodes the relations among these aspects (Eichenbaum& Cohen, 2001) that uniquely support conscious <strong>recollection</strong>(Moscovitch, 2000; Moscovitch & McAndrews, 2002). Insupport <strong>of</strong> this view, Davachi <strong>and</strong> Wagner (2002) found thatencoding <strong>of</strong> the relations among triplets <strong>of</strong> words elicitedgreater hippocampal activation than did rote rehearsal <strong>of</strong>these words, whereas the opposite pattern was observed inthe rhinal <strong>and</strong> parahippocampal cortices.By this account, our findings <strong>of</strong> rhinal cortex activationassociated with successful item recognition <strong>and</strong> hippocampalactivation associated with successful source memorymay reflect the differential reliance <strong>of</strong> these two measureson item versus relational processing (Eichenbaum &Cohen, 2001). However, the fact that encoding activity inthe posterior parahippocampal cortex was sensitive to thesuccessful <strong>recollection</strong> <strong>of</strong> source information suggests thatthe proposed role for the rhinal cortex in item-based encodingmay not generalize to the posterior parahippocampalcortex. Indeed, although researchers have generally assumeda similar function for rhinal <strong>and</strong> parahippocampal corticalregions on the basis <strong>of</strong> parsimony, there has been little workto systematically compare the response properties <strong>of</strong> thesetwo regions (Suzuki, 1999).4.2. Prefrontal encoding activity associated with<strong>familiarity</strong> <strong>and</strong> <strong>recollection</strong>In addition to examining activity within the MTL, weexamined patterns <strong>of</strong> activity within the PFC, based onfindings suggesting that the PFC may contribute disproportionatelyto <strong>recollection</strong> (Davidson & Glisky, 2002;Knowlton & Squire, 1995). However, as shown in Tables 1<strong>and</strong> 2, subsequent memory effects related to both <strong>familiarity</strong><strong>and</strong> <strong>recollection</strong> were observed within the PFC.For example, frontopolar (BA 10) <strong>and</strong> medial orbit<strong>of</strong>rontalregions (BA 11) exhibited subsequent <strong>familiarity</strong> effects.These regions have been implicated in memory encoding(Frey & Petrides, 2000, 2002) <strong>and</strong> they are extensivelyinterconnected with the rhinal cortex, where a subsequent<strong>familiarity</strong> effect was also observed. Although the presentresults do not suggest exactly how these regions contributeto <strong>familiarity</strong>-based recognition, the unique neuroanatomicalconnectivity <strong>of</strong> these areas suggests one possibility. Aswe have described elsewhere (Ranganath & Rainer, 2003),the orbital PFC <strong>and</strong> the rhinal cortex are among a smallset <strong>of</strong> cortical areas that project to the cholinergic nuclei <strong>of</strong>the basal forebrain (Mesulam & Mufson, 1984). Given therole <strong>of</strong> acetylcholine in enhancing synaptic plasticity (Gu,2002) <strong>and</strong> memory consolidation (Hasselmo, 1999), wehave hypothesized that an orbit<strong>of</strong>rontal-rhinal circuit mayact to modulate the encoding <strong>of</strong> items based on their relativenovelty or distinctiveness (Kishiyama & Yonelinas, inpress; Ranganath & Rainer, 2003). This hypothesis presentsone potential mechanism by which orbit<strong>of</strong>rontal <strong>and</strong> rhinalcortical regions may modulate encoding in a way thatsubsequently impacts <strong>familiarity</strong>-based recognition.Activation in many ventrolateral prefrontal areas predictedsubsequent <strong>recollection</strong>. These areas spanned much<strong>of</strong> the left (BA 45/47) <strong>and</strong> right (BA 44) inferior frontalgyri. Finally, we note that activation in the posterior extent<strong>of</strong> the left inferior frontal gyrus (BA 6/44)—an areaidentified in numerous studies <strong>of</strong> verbal memory encoding(Buckner, 2003; Fletcher & Henson, 2001; Ranganath &Knight, 2003; Wagner, 1999)—predicted both subsequent<strong>recollection</strong> <strong>and</strong> <strong>familiarity</strong> (see Fig. 5). The precise contribution<strong>of</strong> these regions to memory encoding, <strong>and</strong> moregenerally to linguistic processing has been a topic <strong>of</strong> extensivedebate (Gold & Buckner, 2002; Thompson-Schill,D’Esposito, Aguirre, & Farah, 1997; Wagner, Pare-Blagoev,Clark, & Poldrack, 2001). Although some findings suggestthat different subregions <strong>of</strong> the left inferior frontal cortexmay implement different encoding processes (Gold &Buckner, 2002; Wagner et al., 2001), analyses on activitywithin these regions did not reveal any reliable qualitativedifferences between contributions <strong>of</strong> these subregions to<strong>recollection</strong> <strong>and</strong> <strong>familiarity</strong> (results available on request).The present findings suggest that damage to the PFC mayaffect <strong>familiarity</strong> <strong>and</strong> <strong>recollection</strong>, in contrast to the viewthat the PFC uniquely contributes to <strong>recollection</strong> (Davidson& Glisky, 2002; Knowlton & Squire, 1995; Manns et al.,2003). Indeed, although not all PFC subregions exhibitedboth subsequent <strong>familiarity</strong> <strong>and</strong> <strong>recollection</strong> effects,most studies <strong>of</strong> patients with PFC lesions typically includepatients with lesions that span multiple subregions (e.g.,Janowsky, Shimamura, & Squire, 1989; McAndrews &Milner, 1991; Rapcsak, Polster, Glisky, & Comer, 1996;Stuss et al., 1994). Little work has been done in such studiesto determine whether patients with PFC lesions exhibit<strong>familiarity</strong> deficits, however several studies have shownthat such patients can exhibit particularly high false alarmrates on recognition tests (Delbecq-Derouesne, Beauvois,& Shallice, 1990; Rapcsak et al., 1998; Rapcsak et al.,
10 C. Ranganath et al. / Neuropsychologia xxx (2003) xxx–xxx1996; Rapcsak, Reminger, Glisky, Kaszniak, & Comer,1999; Schacter, Curran, Galluccio, Milberg, & Bates, 1996;Swick & Knight, 1999). These findings suggest that PFClesions may impair <strong>familiarity</strong>-based recognition. Furtherwork needs to be done to characterize the memory deficitsexhibited by patients with PFC lesions, <strong>and</strong> the degree towhich such deficits can be linked to impairments in specificencoding <strong>and</strong>/or retrieval processes. Nonetheless, theavailable evidence is consistent with the view that PFCimplements executive control processes critical for accurate<strong>recollection</strong> <strong>and</strong> <strong>familiarity</strong>-based recognition memory(Ranganath & Knight, 2003).5. ConclusionsIn summary, the present results are consistent with theview that, although different MTL subregions play a jointrole in the formation <strong>of</strong> complex episodic memories (Fellet al., 2001), each subregion implements distinct computations.Indeed, available evidence from neuroanatomy(Lavanex & Amaral, 2000), neurophysiology (Brown &Aggleton, 2001; Suzuki, 1999), neuroimaging (Davachiet al., 2003; Davachi & Wagner, 2002; Ranganath &D’Esposito, 2001), <strong>and</strong> neuropsychological (Aggleton &Brown, 1999; Eichenbaum & Cohen, 2001) studies is inconsistentwith the view that the hippocampus, rhinal,<strong>and</strong> parahippocampal cortices implement the same types<strong>of</strong> processes. The present findings add to this picture bydemonstrating that <strong>recollection</strong> <strong>and</strong> <strong>familiarity</strong> depend ondifferent MTL subregions.AcknowledgementsSpecial thanks to Chris Moore, Chris May, Chris Rorden,Sarah Trefethen, Keith Widaman, David Woods, <strong>and</strong> BillYund for their assistance, <strong>and</strong> to the reviewers for their helpfulsuggestions. This research was supported by grants fromthe McDonnell-Pew Program in Cognitive Neuroscience,NIMH grants MH63901 <strong>and</strong> MH59352, <strong>and</strong> NIA grantsAG05863 <strong>and</strong> AG15793, a UC Davis New Faculty ResearchGrant, <strong>and</strong> a UC Davis Alzheimer’s Disease Center PilotResearch Grant.ReferencesAggleton, J. P., & Brown, M. W. (1999). Episodic memory amnesia <strong>and</strong>the hippocampal-anterior thalamic axis. Behavioral <strong>and</strong> Brain Sciences,22, 425–444.Aggleton, J. P., & Shaw, C. (1996). 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